Alpha-methylated Phenylalanine Containing Peptide targeting Amyloid beta for Alzheimer's treatment
Disciplines
Biochemistry | Medicinal-Pharmaceutical Chemistry
Abstract (300 words maximum)
Alzheimer’s Disease (AD) is a neurodegenerative illness characterized by a decline in cognition and memory. In the USA, an estimated 6.7 million adults aged 65 and older are currently affected, with projections of 13.8 million by 2060 if the trend continues. AD-related deaths surged by more than 145% from 2000 to 2019. Shockingly, the CDC ranked Alzheimer’s as the 7th leading cause of death in 2019, and it rose to the 5th leading cause in 2023. The Amyloid-Beta (Aβ) hypothesis proposes that the accumulation of Amyloid-Beta (Aβ) peptides in our cerebral cortex causes the formation of senile plaques leading to neuronal cell death. This research aims to develop potent analogs by modifying previously tested peptides for their ability to bind and inhibit the 1-42 Amyloid-Beta (Aβ) peptide. Multiple peptide sequences were modified to incorporate alpha-methylated phenylalanine, which has been demonstrated to enhance inhibitory properties. For synthesizing these c peptides, a CEM Liberty Blue peptide synthesizer was utilized to synthesize solid-phase peptides following standard Fmoc procedures and cleaved with 95% trifluoroacetic acid. The peptides in this study were then measured for their binding affinity with Amyloid-Beta (Aβ) using selected ion monitoring (SIM) based mass spectrometry assay. The dissociation constants (Kd) for Aβ–peptide interactions were estimated based on the dose-response by fixing the Aβ concentration while varying the concentration of the linear and cyclic peptides. The three best linear peptides showed the Kd values of 299, 37, and 8.6 nanomolar (nM), respectively. Moreover, the best cyclic peptide demonstrated a Kd value of 49 nanomolar (nM). One of the alpha methylated phenylalanine containing peptide was synthesized and characterized and expected to show the best binding affinity. This study showed that both linear, cyclic and methylated peptides show promise to be excellent therapeutics in inhibiting amyloid beta.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Alpha-methylated Phenylalanine Containing Peptide targeting Amyloid beta for Alzheimer's treatment
Alzheimer’s Disease (AD) is a neurodegenerative illness characterized by a decline in cognition and memory. In the USA, an estimated 6.7 million adults aged 65 and older are currently affected, with projections of 13.8 million by 2060 if the trend continues. AD-related deaths surged by more than 145% from 2000 to 2019. Shockingly, the CDC ranked Alzheimer’s as the 7th leading cause of death in 2019, and it rose to the 5th leading cause in 2023. The Amyloid-Beta (Aβ) hypothesis proposes that the accumulation of Amyloid-Beta (Aβ) peptides in our cerebral cortex causes the formation of senile plaques leading to neuronal cell death. This research aims to develop potent analogs by modifying previously tested peptides for their ability to bind and inhibit the 1-42 Amyloid-Beta (Aβ) peptide. Multiple peptide sequences were modified to incorporate alpha-methylated phenylalanine, which has been demonstrated to enhance inhibitory properties. For synthesizing these c peptides, a CEM Liberty Blue peptide synthesizer was utilized to synthesize solid-phase peptides following standard Fmoc procedures and cleaved with 95% trifluoroacetic acid. The peptides in this study were then measured for their binding affinity with Amyloid-Beta (Aβ) using selected ion monitoring (SIM) based mass spectrometry assay. The dissociation constants (Kd) for Aβ–peptide interactions were estimated based on the dose-response by fixing the Aβ concentration while varying the concentration of the linear and cyclic peptides. The three best linear peptides showed the Kd values of 299, 37, and 8.6 nanomolar (nM), respectively. Moreover, the best cyclic peptide demonstrated a Kd value of 49 nanomolar (nM). One of the alpha methylated phenylalanine containing peptide was synthesized and characterized and expected to show the best binding affinity. This study showed that both linear, cyclic and methylated peptides show promise to be excellent therapeutics in inhibiting amyloid beta.